Aims:The aim of the study was to compare the efficacy of phenytoin and levetiracetam for seizure prophylaxis in patients with severe traumatic brain injury (TBI).Subjects and Methods:A randomized controlled trial was conducted over a period of 6 months, at a tertiary health care center in Karachi, Pakistan. Patients with TBI were divided into two groups. Patients in Group A were given phenytoin, whereas Group B patients received levetiracetam. The first dose of the drugs was given within 24 h of injury and continued for 7 days. Data were collected using a predesigned pro forma. All the patients who were in a state of persistent coma, had altered mental status, or had clinical signs of seizures underwent a 1-h electroencephalographic (EEG) recording to observe the seizures, the first EEG was done on the 1st day posttrauma and a second one was done on day 7 of drug use, both the EEGs were compared for changes. We also analyzed the patients according to their duration of antiepileptic drug therapy, length of hospital stay, and complications during therapy.Results:One hundred and forty (117 males and 23 females) patients who presented with TBI having a mean age of 29.48 ± 16.24 years were part of the study. The most prevalent cause of brain injury was road traffic accidents in 72.85% patients. There was no significant relationship between the antiepileptic drug used with the initial EEG (P = 0.313) and seizure activity (P = 0.502). However, a significant correlation of the antiepileptic drug used was found with EEG (P = 0.002) and seizure activity (P = 0.014) on follow-up. Patients who took levetiracetam had decreased the incidence of abnormal EEG and seizure activity on follow-up. There was not any correlation between GCS both initially (P = 0.845) and on follow-up (P = 0.104) with the antiepileptic drug used.Conclusion:The incidence of abnormal EEGs and seizure activity in patients with TBI is the same for both levetiracetam and phenytoin for the initial 7 days post-TBI; however, the incidence of seizures is lower for patients who used levetiracetam on the subsequent follow-up.